This application entitled, "Discovering Pathways of Functional Decline: A GWAS Approach" addresses the challenge area (08): Genomics and the specific challenge topic, 08-AG-101: Genetic factors affecting rates of change in disease risk factors with age. The proportion of older adults with functional limitations and disability is high. However, there are currently no interventions that have been proven to prevent disability, and, with the exception of physical activity, our current physiologic understanding has yet to yield interventions that are applicable to most at-risk older adults. In the Health ABC study, a 12-year longitudinal study of physical function in community-dwelling older adults, we have identified four markers which show a strong, graded, and independent association with total mortality and the onset of mobility limitations: grip strength, usual gait speed, IL-6 levels, and forced expiratory volume in 1s (FEV1). Evidence shows that these markers are heritable, and there are a number of on-going activities to identify relevant candidate genes. We propose to take advantage of the unique combination of data from the 1M SNP GWAS scan of the Health ABC cohort with data on the longitudinal trajectories of these 4 key disability markers to identify novel genes that may underlie the change in physical function in older adults. Our specific aims are: 1. To identify genes/genomic regions associated with trajectories of change in four markers strongly related to mortality, morbidity and the onset of disability: muscle strength, walking speed, serum IL-6, and FEV1 in 3,075 participants of the Health ABC Study. 2. To conduct in silico replication and meta-analysis in collaboration with other epidemiologic studies of older persons in which whole genome-wide scan data are also available (CHARGE consortium cohorts -- AGES, the CHS Study, the Framingham Heart Study, ARIC -- and InChianti and the BLSA). This application will support 1 graduate student, 1 post-doctoral fellow and two early career investigators. The identification of novel genes may provide the basis for future intervention development targeting newly identified pathways. Because all of the data for this study are available, the proposed project can be done in a cost-effective and timely manner. With the growth in the number of older adults, it is imperative to identify strategies to prevent disability and promote independence. We propose to identify new genes linked to four strong markers of future disability to provide novel targets for disability prevention.